Skip to main content

Advertisement

SpringerLink
Log in

Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and synaptic dysfunction. Adenosine is an important homeostatic modulator that controls the bioenergetic network in the brain through regulating receptor-evoked signaling pathways, bioenergetic machineries, and epigenetic-mediated gene regulation. Equilibrative nucleoside transporter 1 (ENT1) is a major adenosine transporter that recycles adenosine from the extracellular space. In the present study, we report that a small adenosine analogue (designated J4) that inhibited ENT1 prevented the decline in spatial memory in an AD mouse model (APP/PS1). Electrophysiological and biochemical analyses further demonstrated that chronic treatment with J4 normalized the impaired basal synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses as well as the aberrant expression of synaptic proteins (e.g., NR2A and NR2B), abnormal neuronal plasticity-related signaling pathways (e.g., PKA and GSK3β), and detrimental elevation in astrocytic A2AR expression in the hippocampus and cortex of APP/PS1 mice. In conclusion, our findings suggest that modulation of adenosine homeostasis by J4 is beneficial in a mouse model of AD. Our study provides a potential therapeutic strategy to delay the progression of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

aCSF:

artificial cerebrospinal fluid

AD:

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

AMC:

7-amino-4-methylcoumarin

APP:

amyloid precursor protein

AR:

adenosine receptor

BACE1:

β-site APP-cleaving enzyme 1

BBB:

blood-brain-barrier

BSA:

bovine serum albumin

CNS:

central nervous system

ECL:

enhanced chemiluminescence

ELISA:

enzyme-linked immunosorbent assay

ENTs:

equilibrative nucleoside transporters

ENT1:

equilibrative nucleoside transporter 1

fEPSPs:

field excitatory postsynaptic potentials

GFAP:

glial fibrillary acidic protein

GSK3β:

glycogen synthase kinase 3β

HD:

Huntington’s disease

HRP:

horseradish peroxidase

huAPP:

human amyloid precursor protein

IHC:

immunohistochemical

LTP:

long-term potentiation

LRP1:

lipoprotein receptor-related protein-1

MRI:

magnetic resonance imaging

MWM:

Morris water maze

NGS:

normal goat serum

PAGE:

polyacrylamide gel electrophoresis

PB:

phosphate buffer

PS1:

presenilin-1

RT:

room temperature

SAH:

S-adenosylhomocysteine

SCA3:

spinocerebellar ataxia type 3

SDS:

sodium dodecylsulfate

TBS:

theta burst stimulation

TBST:

Tris-buffered saline with 0.1% Tween-20

TMMC:

transgenic mouse models core

UPS:

ubiquitin proteasome system

References

  1. Ittner LM, Gotz J (2011) Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12:65–72

    Article  CAS  Google Scholar 

  2. Chetelat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, Ellis KA, Szoeke C et al (2010) Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol 67:317–324

    CAS  PubMed  Google Scholar 

  3. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608

    Article  CAS  Google Scholar 

  4. Antonioli L, Csoka B, Fornai M, Colucci R, Kokai E, Blandizzi C, Hasko G (2014) Adenosine and inflammation: what's new on the horizon? Drug Discov Today 19:1051–1068

    Article  CAS  Google Scholar 

  5. Carman AJ, Mills JH, Krenz A, Kim DG, Bynoe MS (2011) Adenosine receptor signaling modulates permeability of the blood-brain barrier. J Neurosci 31:13272–13280

    Article  CAS  Google Scholar 

  6. Dias RB, Rombo DM, Ribeiro JA, Henley JM, Sebastiao AM (2013) Adenosine: setting the stage for plasticity. Trends Neurosci 36:248–257

    Article  CAS  Google Scholar 

  7. Porkka-Heiskanen T, Kalinchuk AV (2011) Adenosine, energy metabolism and sleep homeostasis. Sleep Med Rev 15:123–135

    Article  Google Scholar 

  8. Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, Kaplan DL, Boison D (2013) Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 123:3552–3563

    Article  CAS  Google Scholar 

  9. Cunha RA (2016) How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 139:1019–1055

    Article  CAS  Google Scholar 

  10. Chen JF, Lee CF, Chern Y (2014) Adenosine receptor neurobiology: overview. Int Rev Neurobiol 119:1–49

    Article  Google Scholar 

  11. Albasanz JL, Perez S, Barrachina M, Ferrer I, Martin M (2008) Up-regulation of adenosine receptors in the frontal cortex in Alzheimer’s disease. Brain Pathol 18:211–219

    Article  CAS  Google Scholar 

  12. Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J et al (2015) Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 18:423–434

    Article  CAS  Google Scholar 

  13. Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Goncalves N, Gorlewicz A, Malezieux M et al (2016) Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors. Nat Commun 7:11915

    Article  CAS  Google Scholar 

  14. Orr AG, Lo I, Schumacher H, Ho K, Gill M, Guo W, Kim DH, Knox A et al (2018) Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis 110:29–36

    Article  CAS  Google Scholar 

  15. Laurent C, Burnouf S, Ferry B, Batalha VL, Coelho JE, Baqi Y, Malik E, Mariciniak E et al (2016) A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry 21:97–107

    Article  CAS  Google Scholar 

  16. Mendiola-Precoma J, Padilla K, Rodriguez-Cruz A, Berumen LC, Miledi R, Garcia-Alcocer G (2017) Theobromine-induced changes in A1 purinergic receptor gene expression and distribution in a rat brain Alzheimer’s disease model. J Alzheimers Dis 55:1273–1283

    Article  CAS  Google Scholar 

  17. Qazi TJ, Quan Z, Mir A, Qing H (2017) Epigenetics in Alzheimer’s disease: perspective of DNA methylation. Mol Neurobiol

  18. Sanchez-Mut JV, Aso E, Panayotis N, Lott I, Dierssen M, Rabano A, Urdinguio RG, Fernandez AF et al (2013) DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease. Brain 136:3018–3027

    Article  Google Scholar 

  19. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets—what are the challenges? Nat Rev Drug Discov 12:265–286

    Article  CAS  Google Scholar 

  20. Li B, Gu L, Hertz L, Peng L (2013) Expression of nucleoside transporter in freshly isolated neurons and astrocytes from mouse brain. Neurochem Res 38:2351–2358

    Article  CAS  Google Scholar 

  21. Boison D (2006) Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci 27:652–658

    Article  CAS  Google Scholar 

  22. Huang NK, Lin JH, Lin JT, Lin CI, Liu EM, Lin CJ, Chen WP, Shen YC et al (2011) A new drug design targeting the adenosinergic system for Huntington's disease. PLoS One 6:e20934

    Article  CAS  Google Scholar 

  23. Kao YH, Lin MS, Chen CM, Wu YR, Chen HM, Lai HL, Chern Y, Lin CJ (2017) Targeting ENT1 and adenosine tone for the treatment of Huntington’s disease. Hum Mol Genet 26:467–478

    CAS  PubMed  Google Scholar 

  24. Guitart X, Bonaventura J, Rea W, Orru M, Cellai L, Dettori I, Pedata F, Brugarolas M et al (2016) Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease. Neurobiol Dis 96:47–53

    Article  CAS  Google Scholar 

  25. Liu YJ, Ju TC, Chen HM, Jang YS, Lee LM, Lai HL, Tai HC, Fang JM et al (2015) Activation of AMP-activated protein kinase alpha1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis. Hum Mol Genet 24:787–801

    Article  CAS  Google Scholar 

  26. Liu YJ, Lee LM, Lai HL, Chern Y (2015) Aberrant activation of AMP-activated protein kinase contributes to the abnormal distribution of HuR in amyotrophic lateral sclerosis. FEBS Lett 589:432–439

    Article  CAS  Google Scholar 

  27. Chou AH, Chen YL, Chiu CC, Yuan SJ, Weng YH, Yeh TH, Lin YL, Fang JM et al (2015) T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology 99:308–317

    Article  CAS  Google Scholar 

  28. Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F et al (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617

    Article  CAS  Google Scholar 

  29. Paxinos G, Franklin K (2004) The mouse brain in stereotaxic coordinates: Academic Press. 256 pp.

  30. Bhatt DP, Chen X, Geiger JD, Rosenberger TA (2012) A sensitive HPLC-based method to quantify adenine nucleotides in primary astrocyte cell cultures. J Chromatogr B Analyt Technol Biomed Life Sci 889-890:110–115

    Article  CAS  Google Scholar 

  31. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170

    Article  CAS  Google Scholar 

  32. Gelman S, Palma J, Tombaugh G, Ghavami A (2018) Differences in synaptic dysfunction between rTg4510 and APP/PS1 mouse models of Alzheimer’s disease. J Alzheimers Dis 61:195–208

    Article  CAS  Google Scholar 

  33. Gallagher JJ, Minogue AM, Lynch MA (2013) Impaired performance of female APP/PS1 mice in the Morris water maze is coupled with increased Abeta accumulation and microglial activation. Neurodegener Dis 11:33–41

    Article  CAS  Google Scholar 

  34. Janus C, Flores AY, Xu G, Borchelt DR (2015) Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging 36:2519–2532

    Article  CAS  Google Scholar 

  35. Chang CP, Lee CT, Hou WH, Lin MS, Lai HL, Chien CL, Chang C, Cheng PL et al (2016) Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning. Sci Rep 6:22529

    Article  CAS  Google Scholar 

  36. Tian M, Jarsky T, Murphy GJ, Rieke F, Singer JH (2010) Voltage-gated Na channels in AII amacrine cells accelerate scotopic light responses mediated by the rod bipolar cell pathway. J Neurosci 30:4650–4659

    Article  CAS  Google Scholar 

  37. Arslan G, Kull B, Fredholm BB (1999) Signaling via A2A adenosine receptor in four PC12 cell clones. Naunyn Schmiedeberg's Arch Pharmacol 359:28–32

    Article  CAS  Google Scholar 

  38. Minkeviciene R, Banerjee P, Tanila H (2004) Memantine improves spatial learning in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 311:677–682

    Article  CAS  Google Scholar 

  39. Gruart A, Munoz MD, Delgado-Garcia JM (2006) Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci 26:1077–1087

    Article  CAS  Google Scholar 

  40. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC (2006) Storage of spatial information by the maintenance mechanism of LTP. Science 313:1141–1144

    Article  CAS  Google Scholar 

  41. Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405:955–959

    Article  CAS  Google Scholar 

  42. Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61:340–350

    Article  CAS  Google Scholar 

  43. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136

    Article  CAS  Google Scholar 

  44. Lee HK, Takamiya K, Han JS, Man H, Kim CH, Rumbaugh G, Yu S, Ding L et al (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631–643

    Article  CAS  Google Scholar 

  45. Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL (2000) Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci 20:7258–7267

    Article  CAS  Google Scholar 

  46. Raveendran R, Devi Suma Priya S, Mayadevi M, Steephan M, Santhoshkumar TR, Cheriyan J, Sanalkumar R, Pradeep KK et al (2009) Phosphorylation status of the NR2B subunit of NMDA receptor regulates its interaction with calcium/calmodulin-dependent protein kinase II. J Neurochem 110:92–105

    Article  CAS  Google Scholar 

  47. Wang JQ, Liu X, Zhang G, Parelkar NK, Arora A, Haines M, Fibuch EE, Mao L (2006) Phosphorylation of glutamate receptors: a potential mechanism for the regulation of receptor function and psychostimulant action. J Neurosci Res 84:1621–1629

    Article  CAS  Google Scholar 

  48. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116:201–211

    CAS  PubMed  Google Scholar 

  49. Abel T, Nguyen PV (2008) Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog Brain Res 169:97–115

    Article  CAS  Google Scholar 

  50. Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, Masliah E, Xu H (2012) Alzheimer’s beta-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of beta-amyloid. J Neurosci 32:11390–11395

    Article  CAS  Google Scholar 

  51. Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2007) Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. J Neurochem 103:2462–2470

    Article  CAS  Google Scholar 

  52. Ettcheto M, Petrov D, Pedros I, Alva N, Carbonell T, Beas-Zarate C, Pallas M, Auladell C et al (2016) Evaluation of neuropathological effects of a high-fat diet in a presymptomatic Alzheimer’s disease stage in APP/PS1 mice. J Alzheimers Dis 54:233–251

    Article  CAS  Google Scholar 

  53. Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439

    Article  CAS  Google Scholar 

  54. Salcedo-Tello P, Ortiz-Matamoros A, Arias C (2011) GSK3 function in the brain during development, neuronal plasticity, and neurodegeneration. Int J Alzheimers Dis 2011:189728

    PubMed  PubMed Central  Google Scholar 

  55. Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR, Mills GB (2000) Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A 97:11960–11965

    Article  CAS  Google Scholar 

  56. Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338

    Article  Google Scholar 

  57. Tong L, Thornton PL, Balazs R, Cotman CW (2001) Beta -amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival is not compromised. J Biol Chem 276:17301–17306

    Article  CAS  Google Scholar 

  58. Ettcheto M, Abad S, Petrov D, Pedros I, Busquets O, Sanchez-Lopez E, Casadesus G, Beas-Zarate C, Carro E, Auladell C et al. (2017) Early preclinical changes in hippocampal CREB-binding protein expression in a mouse model of familial Alzheimer’s disease. Mol Neurobiol

  59. Roberson ED, English JD, Adams JP, Selcher JC, Kondratick C, Sweatt JD (1999) The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 19:4337–4348

    Article  CAS  Google Scholar 

  60. Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445

    Article  CAS  Google Scholar 

  61. Conti M, Mika D, Richter W (2014) Cyclic AMP compartments and signaling specificity: role of cyclic nucleotide phosphodiesterases. J Gen Physiol 143:29–38

    Article  CAS  Google Scholar 

  62. Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M (2009) Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 106:16877–16882

    Article  CAS  Google Scholar 

  63. Sierksma AS, Rutten K, Sydlik S, Rostamian S, Steinbusch HW, van den Hove DL, Prickaerts J (2013) Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Neuropharmacology 64:124–136

    Article  CAS  Google Scholar 

  64. Perez-Gonzalez R, Pascual C, Antequera D, Bolos M, Redondo M, Perez DI, Perez-Grijalba V, Krzyzanowska A et al (2013) Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer’s disease. Neurobiol Aging 34:2133–2145

    Article  CAS  Google Scholar 

  65. Prickaerts J, Heckman PRA, Blokland A (2017) Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs 26:1033–1048

    Article  CAS  Google Scholar 

  66. Hao JR, Sun N, Lei L, Li XY, Yao B, Sun K, Hu R, Zhang X et al (2015) L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer’s disease via activating dopamine D1 receptor/PKA signaling pathway. Cell Death Dis 6:e1965

    Article  CAS  Google Scholar 

  67. Coutellier L, Ardestani PM, Shamloo M (2014) Beta1-adrenergic receptor activation enhances memory in Alzheimer’s disease model. Ann Clin Transl Neurol 1:348–360

    Article  CAS  Google Scholar 

  68. Han K, Jia N, Li J, Yang L, Min LQ (2013) Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer’s disease. Mol Med Rep 8:737–740

    Article  CAS  Google Scholar 

  69. Arendash GW, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J et al (2009) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer’s disease mice. J Alzheimers Dis 17:661–680

    Article  CAS  Google Scholar 

  70. Dennissen FJ, Anglada-Huguet M, Sydow A, Mandelkow E, Mandelkow EM (2016) Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau DeltaK280. Proc Natl Acad Sci U S A 113:11597–11602

    Article  CAS  Google Scholar 

  71. Blum D, Gall D, Galas MC, d'Alcantara P, Bantubungi K, Schiffmann SN (2002) The adenosine A1 receptor agonist adenosine amine congener exerts a neuroprotective effect against the development of striatal lesions and motor impairments in the 3-nitropropionic acid model of neurotoxicity. J Neurosci 22:9122–9133

    Article  CAS  Google Scholar 

  72. Dall'Igna OP, Porciuncula LO, Souza DO, Cunha RA, Lara DR (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br J Pharmacol 138:1207–1209

    Article  CAS  Google Scholar 

  73. Ena S, de Kerchove d'Exaerde A, Schiffmann SN (2011) Unraveling the differential functions and regulation of striatal neuron sub-populations in motor control, reward, and motivational processes. Front Behav Neurosci 5:47

    Article  Google Scholar 

  74. Brownlow ML, Benner L, D'Agostino D, Gordon MN, Morgan D (2013) Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer’s pathology. PLoS One 8:e75713

    Article  CAS  Google Scholar 

  75. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017) Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med 9:eaaf6295

    Article  Google Scholar 

  76. Takahashi K, Kong Q, Lin Y, Stouffer N, Schulte DA, Lai L, Liu Q, Chang LC et al (2015) Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease. J Exp Med 212:319–332

    Article  CAS  Google Scholar 

  77. Ke RH, Xiong J, Liu Y, Ye ZR (2009) Adenosine A2a receptor induced gliosis via Akt/NF-kappaB pathway in vitro. Neurosci Res 65:280–285

    Article  CAS  Google Scholar 

  78. Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118:1461–1468

    Article  CAS  Google Scholar 

  79. Gu JG, Nath A, Geiger JD (1996) Characterization of inhibitor-sensitive and -resistant adenosine transporters in cultured human fetal astrocytes. J Neurochem 67:972–977

    Article  CAS  Google Scholar 

  80. Anderson CM, Xiong W, Geiger JD, Young JD, Cass CE, Baldwin SA, Parkinson FE (1999) Distribution of equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporters (ENT1) in brain. J Neurochem 73:867–873

    Article  CAS  Google Scholar 

  81. Boison D (2005) Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist 11:25–36

    Article  CAS  Google Scholar 

  82. Boison D (2007) Adenosine-based cell therapy approaches for pharmacoresistant epilepsies. Neurodegener Dis 4:28–33

    Article  CAS  Google Scholar 

  83. Boison D, Aronica E (2015) Comorbidities in neurology: is adenosine the common link? Neuropharmacology 97:18–34

    Article  CAS  Google Scholar 

  84. Augusto E, Matos M, Sevigny J, El-Tayeb A, Bynoe MS, Muller CE, Cunha RA, Chen JF (2013) Ecto-5′-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. J Neurosci 33:11390–11399

    Article  CAS  Google Scholar 

  85. Barros-Barbosa AR, Ferreirinha F, Oliveira A, Mendes M, Lobo MG, Santos A, Rangel R, Pelletier J et al (2016) Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE). Purinergic Signal 12:719–734

    Article  CAS  Google Scholar 

  86. Cunha RA, Milusheva E, Vizi ES, Ribeiro JA, Sebastiao AM (1994) Excitatory and inhibitory effects of A1 and A2A adenosine receptor activation on the electrically evoked [3H]acetylcholine release from different areas of the rat hippocampus. J Neurochem 63:207–214

    Article  CAS  Google Scholar 

  87. Lopes LV, Cunha RA, Ribeiro JA (1999) Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol 82:3196–3203

    Article  CAS  Google Scholar 

  88. Lopes LV, Cunha RA, Kull B, Fredholm BB, Ribeiro JA (2002) Adenosine A(2A) receptor facilitation of hippocampal synaptic transmission is dependent on tonic A(1) receptor inhibition. Neuroscience 112:319–329

    Article  CAS  Google Scholar 

  89. Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, Borycz J, Rebola N et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26:2080–2087

    Article  CAS  Google Scholar 

  90. Cunha RA, Constantino MC, Sebastiao AM, Ribeiro JA (1995) Modification of A1 and A2a adenosine receptor binding in aged striatum, hippocampus and cortex of the rat. Neuroreport 6:1583–1588

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Yun-Lian Lin for helpful suggestions.

Funding

This research was supported by the Academia Sinica and Ministry of Science and Technology (MOST 104-0210-01-09-02, MOST 105-0210-01-13-01, MOST 106-0210-01-15-02). The Alzheimer & Tauopathies laboratory is supported by Inserm, Université Lille, France Alzheimer, programs d’investissements d’avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), ANR (ADORATAU and SPREADTAU), Fondation pour la Recherche Médicale, Vaincre Alzheimer, Fondation Plan Alzheimer, Lille Métropole Communauté Urbaine, Région Hauts-de-France (COGNADORA), and DN2M. A collaboration between Academia Sinica and Inserm has been promoted thanks to PHC Orchid exchange funding.

Author information

Author notes

  1. Chia-Chia Lee and Ching-Pang Chang contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, 115, Taiwan

    Chia-Chia Lee, Ching-Pang Chang, Hsing-Lin Lai, Sin-Jhong Cheng, Hui-Mei Chen, Yu-Ping Liao & Yijuang Chern

  2. School of Pharmacy, National Taiwan University, Taipei, Taiwan

    Chun-Jung Lin & Yu-Han Kao

  3. Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan

    Sin-Jhong Cheng

  4. Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert research centre UMR-S1172, Lille, France

    Emilie Faivre, Luc Buée & David Blum

  5. Department of Chemistry, National Taiwan University, Taipei, Taiwan

    Jim-Min Fang

Authors
  1. Chia-Chia Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ching-Pang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chun-Jung Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hsing-Lin Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-Han Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sin-Jhong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui-Mei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Ping Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Emilie Faivre
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luc Buée
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jim-Min Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yijuang Chern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yijuang Chern.

Ethics declarations

Conflict of Interest

Yijuang Chern and Jim-Min Fang hold patents in adenosine compounds for the treatment of neurodegenerative diseases.

Electronic Supplementary Material

ESM 1

(DOCX 23.1 MB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, CC., Chang, CP., Lin, CJ. et al. Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 55, 8936–8952 (2018). https://doi.org/10.1007/s12035-018-1030-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1030-z

Keywords

Search

Navigation